Aralkoxyguanidines and aryloxyalkoxyguanidines and salts thereof



United States Patent 3,304,324 ARALKOXYGUANIDINES AND ARYLOXYALK- OXYGUANIDINES AND SALTS THEREOF Edward L. Schumann, Kalamazoo, Mich, assignor to The Upjohn Company, Kalamazoo, Mich, a corporation of Delaware No Drawing. Filed July 16, 1964, Ser. No. 383,231 23 Claims. (Cl. 260-501) This application is a continuation-in-part of my application Serial No. 349,169, filed March 3, 1964, and now abandoned.

This invention relates to novel compounds and to a process for their preparation; it is particularly directed to novel aralkoxyguanidines and aryloxyalkoxy-guanidines, the acid addition salts thereof, and to methods for their preparation.

The novel aralkoxyguanidines and aryloxyalkoxyguanidines are represented by the formula wherein R is selected from the group consisting of aralkyl and aryloxyalkyl, wherein the aryl moiety of R is substituted by a member of the group consisting of hydrogen, alkyl, alkoxy, halogen, nitro and phenyl, and the alkyl groups of R contain from one to three carbon atoms, inclusive; R R R and R are selected from the group consisting of hydrogen and alkyl, wherein the alkyl radicals are particularly those containing from one to four carbon atoms, such as methyl, ethyl, propyl and butyl.

The novel aralkoxyand aryloxyalkoxyguanidines of Formula I exist either in the non-protonated (free base) form or the protonated form depending upon the pH of the environment. They form stable protonates (acid addition salts) on neurtalization with suitable acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, thiocyanic, fluosilicic, acetic, benzoic, salicylic,

glycolic, succinic, nicotinic, tartaric, malei, malic, lactic,

methanesulfonic, and cyclohexanesulfamic acids, and the like. The acid addition salts are useful in upgrading the free bases. The free bases are useful as acid acceptors in neutralizing undesirable acidity or in absorbing an acid as it is formed in a chemical reaction, for example, a dehydrohalogenation reaction in which hydrogen and chlorine, bromine, or iodine, are removed from vicinal carbon atoms.

The thiocyanic acid addition salts of the guanidines of Formula I, when condensed with formaldehyde, form resinous materials useful as pickling inhibitors according to US. Patents 2,425,320 and 2,606,155. The compounds of Formula I also form fluosilicic acid addition salts which are useful as mothproofing agents according to US. Patent 2,205,789.

The novel aralkoxyguanidines (I) and aryloxyalkoxyguanidines (I) of the invention are prepared by reacting an acid addition salt of 2-methyl-2-thiopseudourea (e.g., the sulfate) with an aralkoxyamine or aryloxyalkoxyamine of the formula H (II) wherein R and R have the same meaning as above. The reaction advantageously is effected in the presence of an inert liquid medium such as absolute or aqueous alkanol (e.g., absolute ethanol, 50% aqueous ethanol, 75% aqueous ethanol or 50% aqueous methanol) at temperatures ranging between about 50 and about 100 33 04324 Patented Feb. 14., 1967' C., conveniently reflux temperature, for from about 2 to about 20 hours. The resulting acid addition salt (1) can be converted to the free base form by treatment with aqueous alkali hydroxide, e. g., sodium or potassium hydroxide, and the liberated free base can be converted to acid addition salts by neutralization, e.g., with the acids given above. Acid addition salts can also be formed by metathesis. tion salts of the compounds of Formula I are not readily obtained in the crystalline state (e.g., the hydrochloride of Example 1A below), they can be converted to crystalline acid addition salts such as the nitrate by saturation in aqueous solution with a water-soluble salt, particularly with a water-soluble nitrate such as ammonium nitrate or an alkali-metal nitrate. The process is illustratively represented by the following equation:

wherein R and R have the same meaning as above.

Instead of employing 2-methyl-2-thiopseudourea as the guanylating agent, cyanamide, alkylcyanamide or dialkylcyanamide can be used. Thus, reacting the cyanamide compound with an acid addition salt of an aralkoxyamine or aryloxyalkoxyamine of the formula H (II) wherein R and R have the same meaning as above, yields the corresponding aralkoxyguanidine (I) or aryloxyalkoxyguanidine (I) in the form of an acid addition salt. In general, the reaction can be carried out at temperatures ranging between about 30 and about 200 C., for from 1 to about 20 hours. In many instances, partioularly when the reaction is quite vigorous, it is advantageous to carry out the reaction in the presence of an inert liquid medium such as benzene, toluene, xylene, cumene, cymene, and the like. The acid addition salt thus obtained can, if desired, be converted to the free base form as noted above. The process is illustratively represented by the following equation:

wherein R, R R and R have the same meaning as above.

Instead of employing 2-methyl-2-thiopseudourea, cyan amide, alkylcyanamide or dialkylcyanamide as the guanylating agent, a dialkylcarbodiimide can be used. Reacting a dialkylcarbodiimide with an aralkoxyamine or aryloxyalkoxyamine of the formula able acid, e.g., hydrochloric, hydrobromic or sulfuric,

yield the corresponding acid addition salts. The process utilizing a dialkylcarbodiimide for preparing the above.

For example, in cases where the acid addi-- guanidines (I) is carried out in accordance with the following equation:

wherein R-and R have the same meaning as above, and R and R are alkyl.

The starting compounds embraced by Formula II can 'be prepared by known methods, for example, those disclosed in the following publications:

The novel compounds of Formula I, both in their nonprotonated and protonated forms with pharmacologically acceptable acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, benzoic, salicylic, glycolic, succinic, nicotinic, tartaric, maleic, malic, lactic, methanesulfonic, and cyclohexanesulfamic acids, and the like, exhibit pharmacological activity. The compounds of Formula I in their non-protonated and protonated forms (as above described) exhibit central nervous system stimulating, hypocholesteremic, anorexigenic, vasodilating, and anti-inflammatory activities and are useful in arresting or alleviating central nervous system depression, atherosclerosis, obesity, hunger, hypertension and inflammation in mammals and animals, e.g., mice, rats and birds (e.g., poultry).

The invention can be more fully understood by the following examples which embody the best manner known for carrying it out.

EXAMPLE 1 A. I-benzyloxyguanidine nitrate (I) A mixture of 24.6 g. (0.2 mole) of benzyloxyamine (II) (prepared as in Angew. Chem. 68, 303) and 27.8 g. (0.2 mole) of 2-methyl-2-thiopseudourea sulfate in 150 ml. of absolute ethanol was heated under reflux for 4 hours, then refrigerated and filtered to remove 10.5 g. of

unreacted 2-methyl-2-thiopseudourea sulfate. The filtrate was concentrated under reduced pressure and the syrupy residue was boiled with 100 ml. of acetone for 1 hour to destroy unreacted benzyloxyamine. After evaporation of the acetone, the residue was dissolved in water, rendered alkaline with sodium hydroxide andextracted repeatedly with ether. The combined ether extracts were dried over magnesium sulfate, then mixed with ethereal hydrogen chloride.

The resulting oily l-benzyloxyguanidine hydrochloride was dissolved in 50 ml. of water and the resulting solution Was saturated with ammonium nitrate. The precipitate-d solidwas separated by filtration and washed with a small amount of ice water to give 7.5 g. (16% yield) of product which decomposed at 102 'C. A sample recrystallized from a mixtureof 95% ethanol and anhydrous ether gave small needles of l-benzyloxyguanidine nitrate (I) which decomposed at 102 C.

Analysis.Calcd. for C H N O-HNO C, 42.10; H, 5.30; N, 24.55. Found: C, 42.20; H, 5.09; N, 24.38.

Infrared absorption data supported the structure.

On basifying an aqueous solution of the nitrate with sodium hydroxide or potassium hydroxide, the free base form, l-benzyloxyguanidine, is obtained.

B. I-benzyloxyguanidine (I) To a stirred suspension of 200 g. (1.25 moles) of benzyloxyamine hydrochloride in 1.25 l. of toluene under an atmosphere of nitrogen, 52.5 g. (1.25 moles) of cyanamide was added. The mixture was heated under reflux, and shortly after the initiation of reflux, the insoluble solid benzyloxyamine hydrochloride was. converted to an insoluble oil, l-benzyloxyguanidine hydrochloride. Refiuxing was continued for 2 hours. The toluene was evaporated under reduced pressure, and the gummy residue was suspended in 1.5 l. of water and basified with aqueous sodium hydroxide. Crystallization occurred rapidly following the addition of base; the suspension was thoroughly chilled, and the crystalline product was collected, washed with water and dried to give 148 gm. (72% yield) of l-benzyloxyguanidine (I) having a melting point of 103 to 106 C.

The hydrochloric, hydrobromic and sulfuric acid addition salts of the above produced free base, 'l-benzyloxyguanidine, are prepared by adding ethereal hydrogen chloride, hydrogen bromide and sulfuric acid, respectively, to a solution of the free base in ethyl acetate.

By neutralization with cyclohexanesulfamic acid, the free base l-benzyloxyguanidine was converted to its cyclohexanesulfamate (I), melting at 106 to 108 C.

Analysis.Calcd. for C H N O-C H NO S: C, 48.82; H, 7.02; N, 16.27; S, 9.31. Found: C, 48.95; H, 7.16; N, 16.16; S, 9.18.

EXAMPLE 2 1 -(2-phenyleth0xy guanidine and cyclolzexanesulgamate thereof (1) Following the procedure of Example 1B but substituting 2-phenylethoxyamine hydrochloride (II) (J. Med. Pharm. Chem. 4, 51) for benzyloxyamine hydrochloride (II) and substituting benzene for toluene, and maintaining the reaction mixture between 70 and 75 C. for 2 hours, yielded 1-(2-phenylethoxy)guanidine (I), melting at 77 to 78 C.

Analysis.-Cal'cd. for C H N O: C, 60.31; H, 7.31; N, 23.45. Found: C, 60.45; H, 7.33; N, 23.67.

The free base was neutralized with cyclohexanesulfamic acid to obtain its cyclohexanesulfamate (I), melting at 91 to 93 C.

Analysfs.Calcd. for C9H13N3O'C6H13NO3S: C, H, 7.31; N, 15.63; S, 8.95. Found: C, 50.28; H, 7.25; N, 15.56; S, 9.19.

EXAMPLE 3 1 -(1 -phenyleth0xy guanidine and cyclohexanesulyamate thereof (I) 1- (S-phenylpropoxy guanidine nitrate (I) The corresponding free base (11), prepared from 18.8

g. (0.1 mole) of S-phenylpropoxyamine hydrochloride (Helv. Chim. Acta 45, 1381) by treatment with alkali, was dissolved in ml. of 50% aqueous methanol, To this solution, 13.9 g. (0.1 mole) of 2-rnethyl-2-thiopseudourea sulfate was added. and the mixture was heated under reflux for 6 hours, then evaporated to dryness under reduced pressure. The residue was dissolved in 500 ml. of 50% aqueous methanol and the solution was saturated with ammonium nitrate. Methanol was evaporated on the steam bath under an air stream, and the remaining aqueous solution was refrigerated. The solid that precipitated was separated by filtration and recrystallized twice from a mixture of methyl ethyl ketone and ethyl acetate to give 13 g. (51% yield) of 1-(3- phenylpropoxy)-guanidine nitrate (I) as white needles which decomposed sharply at 111 C.

Analysis.Calod. for C H N O-HNO C, 46.87; H, 6.29; N, 21.86. Found: C, 46.67; H, 6.31; N, 22.07.

Infrared spectra supported the structure.

On basifying an aqueous solution of the nitrate with sodium hydroxide or potassium hydroxide, the free base form, 1-(3-phenylpropoxy)guanidine, is obtained.

EXAMPLE 5 1-(4-methylbenzyl0xy)guanidine nitrate (1) Ten grams (0.0575 mole) of 4-methylbenzyloxyamine hydrochloride was converted to its free base (II) [1. Chem. Soc. 229, (1960)] with alkali. The free base was mixed with 300 ml. of 50% aqueous ethanol and 8 g. (0.0575 mole) of 2-methyl-2-thiopseudourea sulfate, and the mixture was heated under reflux for 16 hours. Solvent was removed under reduced pressure. The residue was dissolved in 50 ml. of water and the solution was saturated with ammonium nitrate. The solid that precipitated was recrystallized consecutively from absolute ethanol-anhydrous ether and isopropyl alcohol-anhydrous ether but remained impure. Accordingly, the free base was regenerated and the nitrate salt was reformed as before to give 611 mg. of 1-(4-tmethylbenzyloxy)guanidine nitrate (I) which decomposed at 105 C.

Analysis.-Calcd. for C H N O-HNO C, 44.62; H 5.83; N, 23.13. Found: C, 44.53; H, 5.89; N, 22.82.

Infrared spectra supported the structure.

On basifying an aqueous solution of the nitrate with sodium hydroxide or potassium hydroxide, the free base form, 1-(4-methy1benzyloxy)guanidine, is obtained.

EXAMPLE 6 1- (4-meth0xybenzyl0xy glmnidine nitrate (I) Four grams (0.02 mole) of 4-methoxybenzyloxyamine hydrochloride was converted with alkali to the free base (II) [1. Chem. Soc. 3915 (1962)] and then to 1-(4- methoxybenzyloxy)guanidine nitrate (I) in the manner described in Example 5. The compound decomposed at 105 C.

Analysis.Calcd. for C H N O HNO C, 41.86; H, 5.46; N, 21.70. Found: C, 41.03; H, 5.44; N, 22.20.

Infrared spectra supported the structure.

On 'basifying an aqueous solution of the nitrate with sodium hydroxide or potassium hydroxide, the free base form, 1-(4-methoxybenzyloxy)guanidine, is obtained.

EXAMPLE 7 1-(4-chl0r0benzyl0xy)guanidine nitrate (1) Thirty grams (0.15 mole) of 4-chlorobenzy1oxyamine hydrochloride was converted to the free base (II) (Can. J. Chem. 38, 343). The free base was dissolved in 500 ml. of 75% ethanol, and the solution was treated with 21.6 g. (0.15 mole) of 2-methyl-2-thiopseudourea sulfate and heated under reflux for 16 hours. Upon cooling, 5 g. of white solid precipitated and was removed by filtration and discarded. The filtrate was evaporated under reduced pressure and the residue was dissolved in a mixture of 200 ml. of ethanol and 50 m1. of water, then saturated with ammonium nitrate. The precipitated product was recrystallized twice from methanol to give 8 g. yield) of white 1-(4-chlorobenzyloxy)guanidine nitrate (I) which decomposed at 138 C.

Analysis.Calcd. for C H ClN O-HNO C, 36.58; H, 4.22; N, 21.33; Cl, 13.50. Found: C, 36.68; H, 4.59; N, 21.01; Cl, 13.63.

Infrared spectra supported the structure.

On basifying an aqueous solution of the nitrate with sodium hydroxide or potassium hydroxide, the free base form, 1-(4-chlorobenzyloxy)guanidine, is obtained.

Following the procedure of Example 1B but employing 3 g. of 4-chlorobenzyloxyamine hydrochloride, 0.65 g. of cyanamide, and 30 ml. of toluene, yielded 1-(4- chlorobenzyloxy)guanidine hydrochloride. The latter was treated with ammonium nitrate by the procedure described in Example 7 to obtain 3.1 g. of 1-(4-ch1orobenzyloxy)guanidine nitrate (I), melting at 144 C. with decomposition.

EXAMPLE 7A 1-(2,6-dichl0r0benzyl0xy)guanidine hydrochloride (I) (a) N- (2,6 DICHLOROBENZYLOXY) PH'IHALIMIDE A solution of 39.1 g. (0.2 mole) of 2,6-dichlorobenzyl chloride, 32.6 g. (0.2 mole) of N-hydroxyphthalimide, and 61 ml. of triethylamine in 300 ml. of dimethylformamide was stirred and warmed on a steam bath for 70 minutes, cooled and diluted with 500 ml. of water to give 60.5 g. of N-(2,6-dichlorobenzyloxy)phthalimide, having a melting point of 167 to 168 C. Recrystallization from ethanol did not change the melting point.

Analysis.Calcd. for C H Cl NO C, 55.92; H, 2.82; C1, 22.01; N, 4.35. Found: C, 55.67; H, 3.03; C1, 22.25; N, 4.26.

The infrared and ultraviolet spectra were consistent with the structure.

(b) 2,G-DICHLOROBENZYLOXYAMINE HYDROCHLORIDE A suspension of 55 g. (0.17 mole) of N-(2,6-dichlorobenzyloxy)phthalimide [from (a), above] in 500 ml. of methylene chloride was treated with 8.6 g. of hydrazine hydrate in a small volume of methanol and stirred for 23 hours at room temperature. Solid material was removed by filtration and washed with methylene chloride. The combined filtrate and washings were evaporated to dryness under reduced pressure and the residue was extracted with ether. The ethereal extracts were acidified with an isopropyl alcohol solution of hydrogen chloride to give 38.2 g. of product, which melted at 199 to 201 C. with decomposition. Recrystallization from a mixture of methanol and ethyl acetate gave 27.2 g. of 2,6 'dichlorobenzyloxyamine hydrochloride, melting at 206 C. with decomposition.

Analysis.-Calcd. for CqHqClgNO'HClZ C, 36.79; H, 3.53; Cl, 46.55; N, 6.13. Found: C, 37.21; H, 3.51; Cl, 46.50; N, 6.31.

The infrared and ultraviolet spectra were consistent with the structure.

(0) 1-(2,6-DICHLOROBENZYLOXY)GUANIDINE HYDROCHLORIDE (I) A toluene suspension of 11.4 g. (0.05 mole) of 2,6-dichlorobenzyloxyamine hydrochloride [from (b), above] and 2.1 g. of cyanamide was vigorously stirred and refluxed under nitrogen for an hour. The solvent was removed by evaporation under reduced pressure; trituration of the residue with ethyl acetate gave 12.42 g. of crude 1-(2,6-dichlorobenzyloxy)guanidine hydrochloride melting at 109 to 111 C. The crude salt was suspended in water, and the mixture was cooled and basified with sodium hydroxide. The thus obtained free base, 1-(2,6- dichlorobenzyloxy)guanidine (I), melting at 145 to 148 C., was dissolved in a mixture of methylene chloride and ethyl acetate. The solution was clarified with Celite (diatomaceous earth) and was then acidified with an isopropyl alcohol solution of hydrogen chloride to give 9.5 g. of hydrochloride, which melted at 128 to 130 C. An analytical sample was recrystallized from a mixture of methanol and isopropyl alcohol to give pure 1-(2,6-dichlo-robenzyloxy)guanidine hydrochloride (I), with a melting point of 131 to 132 C.

Analysis.Calcd. for C H Cl N O-HCl: C, 35.51; H, 3.72; N, 15.53; Cl, 39.32. Found: C, 35.69; H, 3.76; N, 15.34; Cl, 38.82.

On basifying an aqueous solution of the hydrochloride with sodium hydroxide or potassium hydroxide, the free base form, 1-(2,6-dichlorobenzyloxy)guanidine, is obtained.

EXAMPLE 8 1-benzhydryl0xyguanidine nitrate (I) Benzhydryloxyamine (II), obtained from 23.6 g. (0.1 mole) of its hydrochloride (prepared by reacting N-hydroxyphthalimide with benzhydryl chloride in the presence of dimethylformamide and triethylamine to give N-benzhydryloxythalimide, followed by reaction with hydrazine hydrate in the presence of dimethylformamide and methanol, and then by treatment with hydrochloric acid) by treatment with alkali, was dissolved in 100 ml. of 50% ethanol. The solution was treated with 13.9 g. (0.1 mole) of 2-methyl-2-thiopseudourea sulfate and heated under reflux for 4 hours. Solvent was removed under reduced pressure. The gummy residue was dissolved in 100 ml. of water and the solution was saturated with ammonium nitrate. The precipitate was separated by filtration and recrystallized twice from methyl ethyl ketone to give 3.6 g. (12% yield) of 1-benzhydryloxyguanidine nitrate (I) as fine, white needles which decom- EXAMPLE 9 I -(3,3-diphenylprop0xy) guanidine nitrate (I 3,3-diphenylpropoxyamine (II), obtained from 15.5 g. (0.069 mole) of its hydrochloride (prepared by reacting benzohydroxamic acid with 3,3-diphenylpropyl bromide in an ethanolic solution of sodium hydroxide to give 3,3- diphenyl-l-benzamidooxypropane, followed by hydrolysis with ethanolic hydrogen chloride) by treatment with alkali, was dissolved in 100 ml. of 50% ethanol. The solution was treated with 9.5 g. (0.069 mole) of 2-methyl- Z-thiopseudourea sulfate and heated under reflux for 8 hours. Solvent was removed under reduced pressure. The gummy residue was dissolved in 300 ml. of methanol and 100 ml. of water, and the solution was saturated with ammonium nitrate and refrigerated. The supernatant solution was decanted from a small amount of precipitated oil and solid, diluted with 2 1. of water and again refrigerated. The precipitated solid was separated by filtration, washed with water and recrystallized from ethyl acetate to give 9.5 g. (43% yield) of 1-(3,3-diphenylpropoxy)guanidine nitrate (I), which decomposed at 116 C.

Analysis.Calcd. for C H N O-HNO C, 57.82; H, 6.07; N, 16.86. Found: C, 57.73; H, 6.00; N, 17.09.

Infrared spectra supported the structure.

On basifying an aqueous solution of the nitrate with sodium hydroxide or potassium hydroxide, the free base form, 1-(3,3-diphenylpropoxy)guanidine, is obtained.

EXAMPLE 10 A. I-(Z-phenoxyethoxy)guanidine nitrate (I) Nineteen grams (0.1 mole) of 2-phenoxyethoxyamine hydrochloride was converted to the free base (II) (J. Amer. Chem. Soc. 70, 2829) with alkali. The free base was mixed with 100 ml. of ethanol and 13.9 g. (0.1 mole) of 2-methyl-2-thiopseudourea sulfate. The mixture was heated under reflux for 6 hours, then evaporated to dryness on the steam bath under reduced pressure. The gummy residue was dissolved in 500ml. of 50% aqueous methanol and the solution was saturated with ammonium nitrate. Methanol was evaporated on a steam bath under an air stream and the remaining solution was refrigerated. The precipitated solid was separated by filtration and recrystallized from ethyl acetate to give 9.5 g. (37% yield) of white product, 1-(2-phenoxyethoxy)guanidine nitrate (I) which decomposed sharply at 104 C.

Anatysis.--Calcd. for C H N O -HNO C, 41.86; H, 5.46; N, 21.70. Found: C, 41.66; H, 5.73; N, 21.58.

Infrared spectra supported the structure.

On basifying an aqueous solution of the nitrate with sodium hydroxide or potassium hydroxide, the free base form, 1-(2-phenoxyethoxy)guanidine is obtained.

B. 1-(2-phenoxyeth0xy guanidine and cyclohexanesulfamate thereof (1) A mixture of 20 g. (0.105 mole) of 2-phenoxyethoxyamine hydrochloride (II) and 4.4 g. (0.105 mole) of cyanamide in toluene was heated under reflux to give oily 1-(Z-phenoxyethoxy)guanidine hydrochloride (1). Basification of the hydrochloride afforded 17.45 g. yield) of 1-(2-phenoxyethoxy)guanidine (I), with a melting point of 119 to 121 C. Recrystallization from isopropyl alcohol gave pure 1-(2-phenoxyethoxy)guanidine (I), melting at 121 to 123 C.

Analysis.Calcd. for C I-1 N 0 C, 55.37; H, 6.71; N, 21.53. Found: C, 55.45; H, 6.66; N, 21.72.

Infrared and ultraviolet spectra supported the structure.

By neutralization with cyclohexanesulfamic acid, the

free base, 1-(2-phenoxyethoxy)guanidine was converted to its cyclohexanesulfamate (I). This salt exhibited double melting point behavior; it first melted at 85 to 87 C.,

then resolidified and melted at 9.5 to 96 C.

EXAMPLE 11 1-(1-methyl-2-phenylethoxy )guanidine and cyclohexanesulfamate thereof (1) Following the procedure of Example 113 but substituting 1-methyl-Z-phenylethoxyamine hydrochloride (II) (Helv. Chim. Acta 45, 1381) for benzyloxyamine hydrochloride (II), and maintaining the temperature of the reaction mixture at 83-84 C., yielded l-(l-methyl-Z- phenylethoxy)guanidine (I). The free base was neutrolized with cyclohexanesulfamic acid to obtain its cyclohexanesulfamate (I), melting point 128 to 130 C.

A nnlysis.-Calcd. for C H N O C l-1 N0 5: 51.59; H, 7.58; N, 15.04; S, 8.61. H, 7.62; N, 15.08; S, 8.74.

Following the procedures of Example 1 (A and B) but substituting for the starting materials employed therein, the following free bases or acid addition salts of Formula II:

(1) S-methylbenzyloxyamine (Belgian Patent 612,879), (2) 4-ethylbenzyloxyamine [1. Chem. Soc., 3915 (3) 4-isopropylbenzyloxyamine U, Chem. Soc, 3915 (4) 4-butylbenzyloxyamine [1. Chem. Soc., 3915 (5) 4-sec.butylbenzyloxyamine [1. Chem. 800., 3915 (6) 4-tert.butylbenzyloxyamine [1. Chem. Soc., 3915 (7) Z-phenylpropoxyarnine (Helv. Chim. Acta, 45,

(8) l-naphthylrnethoxyamine [1. Chem. Soc., 229

(9) Z-naphthylmethoxyamine [1. Chem. Soc, 229

r (10) Z-methyl-l-naprthy1methoxyamine [1. Chem. Soc.,

C, Found: C, 52.06;

(11) 4-methyl-l-naphthylmethoxyamine [1. Chem. Soc.,

(12) 2-chlorobenzylamine (Belgian Patent 612,879),

(13) 4-bromobenzyloxyamine [1. Chem. Soc., 229

(14) 2,4-dichlorobenzyloxyamine (Can. 1. Chem., 38,

(15 3,4-dichlorobenzyloxyamine (Can. 1. Chem, 38,

(16) 1-chloro-2-naphthylmethoxyamine [1. Chem, Soc.,

(17) 1-bromo-2-naphthylmethoxyamine [1. Chem. Soc.,

(18) 4-brorno-l-naphthylmethoxyamine [1. Chem. Soc.,

(19) 2-nitrobenzyloxyamine [1. Chem. Soc., 229

(20) 4-nitrobenzyloxyamine [1. Chem. Soc, 229

(1960)], and

(21) 2-(3,4,5 trimethoxyphenyl)ethoxyamine (1. Med.

Pharm. Chem. 4, 51),

yields, respectively, the free bases or acid addition salts of the following products of Formula I:

(1) 1-(3-methylbenzyloxy) guanidine,

(2) 1-(4-ethylbenzyloxy)guanidine,

(3) 1- (4-isopropylbenzyloxy) guanidine,

(4) 1-(4-butylbenzyloxy)guanidine,

(5) 1-(4-sec.but3. lbenzyloxy) guanidine,

(6) 1-(4-tert.butylbenzyloxy)guanidine,

(7) I-(Z-phenylpropoxy)guanidine,

(8) 1-( l-naphthylmethoxy) guanidine,

(9) 1-(2-naphthylmethoxy) guanidine,

(l0) 1-( 2-methyl-1-naphthylmethoxy) guanidine,

(11) 1-(4-methy1-1-naphthylmethoxy) guanidine,

(12) 1-(2-chlorobenzyloxy) guanidine,

( 13 1-(4-bromobenzyloxy guanidine,

(14) 1-(2,4-dichlorobenz.yloxy)guanidine,

(15) 1-(3,4-dich1orobenzyloxy guanidine,

( 16) 1-(1-chloro-2-naphthylmethoxy)guanidine,

( 17) 1-( l-bromo-Z-naphthylmethoxy) guanidine,

(18) 1-(4-brorno-1-naphthylmethoxy) guanidinc,

(l9) 1- 2-nitrobenzy1oxy guanidine,

(20) 1-(4-nitrobenzyloxy) guanidine. and

(21) 1- 2- 3 ,4,S-trimethoxyphenylethoxy) ]guanidine.

EXAMPLE 12 1-(4-phenylbenzyl0xy)guanidine (I) Following the procedure of Example 7A(a) but substituting 4-phenylbenzyl chloride for 2,6-dichlorobenzyl chloride, there was obtained N (4 phenylbenzyloxy) phthalimide. The latter was reacted with hydrazine hydrate according to the procedure of Example 7A(b) to obtain 4-phenylbenzyloxyamine, which in turn was treated with hydrogen chloride to obtain 4-phenylbenzyloxyamine hydrochloride (11).

A toluene suspension of 8.85 g. (0.038 mole) of 4- phenylbenzyloxyamine hydrochloride (II) and 1.58 g. (0.038 mole) of cyanamide was stirred under nitrogen and heated under reflux for 6 hours. The solvent was evaporated from the reaction mixture under reduced pressure and the residue was extracted with hot ethanol. The ethanol solution was filtered and the filtrate was concentrated until crystallization occurred. After cooling, 1.41 g. of solid was removed by filtration. The filtrate was evaporated to dryness, leaving 9.4 g. of a viscous residue which solidified on standing for about 16 hours. This residue was dissolved in methanol and the solution was basified with sodium methoxide The resulting precipitate was diluted with water and the mixture was stirred. The solid weighed 6.3 g. after being collected, washed with water, and dried; it had a melting point of 156 to 166 C. The solid was dissolved in ethyl acetate and the solution was clarified with diatomaceous earth and concentrated; 3.74 g. of crystalline product was ob- 10 tained therefrom that melted at 175 to 177 C. The product was recrystallized from ethanol to give 3.22 g. of pure 1-(4-phenylbenzyloxy)guanidine (I) having a melting point of 175 to 176 C.

Analysis.Calcd. fQr C14H15N3OI C, H, N, 17.42. Found: C, 69.73; H, 6.40; N, 17.69.

The infrared and ultraviolet spectra were consistent with the structure.

The hydrochloric, h-ydrobromic and sulfuric acid addition salts of the above produced free base, 1-(4-phenylbenzyloxy)guanicline, are prepared by adding ethereal hydrogen chloride, hydrogen bromide and sulfuric acid, respectively, to a solution of the free base in ethyl acetate.

EXAMPLE 13 1- [2-(4-biphenylyl0xy eth0xy1guanidine (I) (a) 2(4-BIPHENYLYLOXY)ETHYL CHLORIDE To a chilled suspension of 26 g. (0.12 mole) of 2-(4- biphenylyloxy)ethanol (J. Amer. Chem. Soc., 57, 527) in 200 ml. of benzene containing 9.75 ml. of pyridine, was slowly added 9 ml. of thionyl chloride with vigorous stirring. The mixture was stirred briefly at room temperature, heated under reflux for 3 hours, washed with water and then with brine, and dried over magnesium sulfate. The solution was concentrated and the benzene was displaced with methanol. On cooling, 22.85 g. of material melting at to 102 C. was obtained. Recrystallization from methanol gave an analytical sample of 2-(4-biphenylyloxy)ethyl chloride, with a melting point of 101 to 103 C.

Analysis.Calcd. for C H C10: C, 72.26; H, 5.63; C1, 15.24. Found: C, 72.60; H, 5.42; C1, 14.87.

(b) N- [-2 (4-BIPHENYLYLOXY) ETHOXY] PHTHALIMIDE A solution of 28.2 g. (0.12 mole) of 2-(4-biphenylyloxy)ethylchloride [prepared as in (a), above], 19.8 g. of N-hydroxyphthalimide, and 37 ml, of triethylamine in 185 ml. of dimethylformamide was stirred and heated on the steam bath for 28 hours. The solution Was cooled and diluted with stirring with 250 ml. of Water. The resulting solid was collected, washed with water, dissolved with methylene chloride, and the solution was dried over sodium sulfate. The methylene chloride was displaced with ethanol and the solution was allowed to cool, whereupon 11.1 g. of product, melting at 168 to 170 C., was recovered. Recrystallization of a portion from a mixture of methylene chloride and ethanol gave an analytical sample of N [2 (4-biphenylyloxy)ethoxy1phthalimide with a melting point of 170 to 171 C.

Analysis.-Calcd. 01 C22H17NO4I C, H, Found: C, 73.73; H, 5.10.

The infrared and ultraviolet spectra were consistent with the expected structure.

(e) 2 (4-BIPHENYLYLOXY) ETHOXYAMINE HYDROCHLORIDE A stirred solution of 9.1 g. (0.025 mole) of N-[2-(4- biphenylyloxy)ethoxy]phthalimide [from (b), above] in 200 ml. of methylene chloride was treated with 1.27 g. of hydrazine hydrate in 5 ml. of methanol. After 5 hours the precipitate was filtered off and washed with methylene chloride. The combined filtrate and washings were evaporated to dryness under reduced pressure. The residue was extracted with ethyl acetate and the extracts were washed with water, dried over potassium carbonate and magnesium sulfate, and acidified with an isopropyl alcohol solution of hydrogen chloride, to give 5.6 g. of 2-(4-biphenylyloxy)ethoxyamine hydrochloride, which melted at 227 C. with decomposition. The hydrochloride was converted with alkali into its free base, which had a melting point of 128.5 to C. after recrystallization from isopropyl alcohol. The free base was reconverted with hydrogen chloride to its hydrochloride which melted at 225 to 227 C. A sample Was recrystallized from a mixture of ethanol and isopropyl alcohol to give an analytical sample of 2-(4-biphenylyloxy) 11 ethoxyamine hydrochloride having a melting point of 225 to 226 C.

Analysis.--Calod. for C H NO -HCl: C, 63.27; H, 6.07; N, 5.27; Cl, 13.34. Found: C, 63.23; H, 6.06; N, 5.59; Cl, 13.30.

The infrared and ultraviolet spectra were consistent with the structure.

(11) 1[2-(4-BIPHENYLYLOXY)ETHOXY] GUANIDI-NE (I) A toluene suspension containing 4 g. (0.15 mole) of 2(4-hiphenylyloxy)ethoxyarnine hydrochloride (II) [from (c), above] and 0.64 g. (0.015 mole) of cyanamide was stirred under nitrogen and heated under reflux for 4 hours. After being allowed to cool, the solid was collected, washed with ethyl acetate and dried, to yield 4.09 g. of 1- [2-(4-biphenylyloxy)ethoxy] guanidine hydrochloride, melting at 174. to 176 C. with decomposition. This material was dissolved in methanol and basified with sodium methoxide. The resulting suspension was diluted with water and the resulting solid was collected, washed with aqueous methanol, and dried, to give 2.36 g. of free base, melting at 185 to 187.5 C. Recrystallization from a mixture of ethanol and isopropyl alcohol gave 2.21 g. of an analytical sample of 1-[2-(4-biphenylyloxy)ethoxy] guanidine (I), having a melting point of 186.5 to 188 C.

Analysis.Calcd. for C H N O C, 66.40; H, 6.32; N, 15.49. Found: C, 66.09; H, 6.55; N, 15.72.

The infrared and ultraviolet spectra were consistent with the structure.

The hydrochloric, hydrobromic and sulfuric acid addition salts of the above produced free base, 1-[2-(4-biphenylyloxy)ethoxy]guanidine, are prepared by adding ethereal hydrogen chloride, hydrogen bromide and sulfuric acid, respectively, to a solution of the free base in ethyl acetate.

EXAMPLE 14 1'-benzyl0xy-1-methylguanidine hydrochloride (I) A toluene suspension of 7.56 g. (0.044 mole) of N- rnethyl-benzyloxyamine hydrochloride (II) (Helv. Chim. Acta 45, 1381) and 1.83 g. of cyanamide was stirred at room temperature. After an hour the solid became gummy. The mixture was heated under reflux for 1.25 hours, during which period the gummy material solidified. This was collected, washed with benzene and dried, to yield 8.37 g. of crude product, which melted at 135 to 143 C. This material was purified by dissolving it in water, adding sodium hydroxide and sodium chloride, and chilling to give 3.58 g. of product with a melting point of 182 to 184 C. Recrystallization from isopropyl alcohol gave an analytical sample of l-benzyloxy-lmethylguanidine hydrochloride (I) with a melting point of 183 to 183.5 C.

Analysis.Calcd. for C H N O-HCl: C, 50.12; H, 6.54; N, 19.48; Cl, 16.44. Found: C, 50.22; H, 6.04; N, 19.93; Cl, 16.54.

The infrared and ultraviolet spectra were consistent with the structure.

On basifying a methanolic solution of the hydrochloride with sodium methoxide, the free base form, l-benzyloxyl-methylguanidine, is obtained.

EXAMPLE 15 1-benzyl0xy-3,3-dimeihylgurmidine cyclohexanesulfamaze (I) 'A solution of 16 g. (0.1 mole) of benzyloxyamine hydrochloride (II) and 7 g. of dimethylcyanamide was stirred under nitrogen and heated in an oil bath at 150 to 160 C. for 1.5 hours. The resulting gummy material was suspended in water and basified; the oil that separated was extracted with ether and the extracts were Washed with water, dried, and the solvent was evaporated to dryness under reduced pressure to obtain 15.5 g. of oil. The oil was dissolved in 155 ml. of ethyl acetate and the solution was treated with a solution of 14.4 g. of cyclo- 12 hexanesulfa-mic acid in 150 ml. of acetone, to give 24.2 g. of 1-benzyloxy-3,3-dimethylguanidine cyclohexanesulfamate (I), melting at 119 to 122 C.

Analysis.Calcd. for C l-l N O-C H NO S: C, 51.59; H, 7.58; N, 15.04; S, 8.61. Found: C, 51.50; H, 7.61; N, 15.05; S, 8.60.

The infrared and ultraviolet spectra were consistent with the structure.

On basifying an aqueous solution of the cyclohexanesulfamate with sodium hydroxide or potassium hydroxide, the free base form, 1-benzyloxy-3,3-dimethylguanidine, is obtained.

Following the procedure of Example 15 but substituting ethylcyanarnide and diisobutylcyanamide for dirnethylcyanamide, there are obtained 1-benzyloxy-3-ethylguanidine cyclohexanesulfamate and l-benzyloxy-3,3-diisooutylguanidine cyclohexanesulfamate, respectively. By basifying an aqueous solution of each salt, the corresponding free base is obtained.

EXAMPLE 16 l-benzyl0xy-Z,3-diis0pr0pyIguanidine hydrochloride (1) A mixture of 12.3 g. (0.10 mole) of benzyloxyamine, 6.3 g. (0.05 mole) of diisopropylcarbodiimide, and 10 ml. of tertbutyl alcohol was heated on a steam bath for 14.5 hours. Volatile materials were removedby heating under reduced pressure C. at 10 mm. Hg) to leave a blue oil. The oil was dissolved in acetone, and the solution was briefly heated under reflux and then evaporated to dryness to leave 10.8 g. of pale green oil. This was dissolved in acetone and the solution was treated with a solution of 8.95 g. of cyclohexanesulfamic acid in acetone. On chilling for about 16 hours, only a trace of insoluble material separated and was removed by filtration. The filtrate was evaporated to dryness, leaving an oil which was distributed between ether and Water. The aqueous layer was separated, basified and extracted with ether. The ether extract was dried with potassium carbonate and magnesium sulfate and evaporated to dryness, leaving 5.95 g. of yellow oil. Dissolving this in a mixture of ethyl acetate and ether, and acidifying this solution with an isopropyl alcohol solution of hydrogen chloride, gave 5.8 g. of product, which melted at 112 to 121 C. Recrystallization from a mixture of isopropyl alcohol and ethyl acetate gave pure 1-benzyloxy-2,3-di isopropylguanidine hydrochloride (1) with a melting point of 125 to 126 C.

Analysis.-Calcd. for CMH23N3O-HC1: c, 58.83; H, 8.46; N, 14.70 or, 12.41. Found: c, 58.66; H, 8.48; N, V

The infrared and ultraviolet spectra were consistent with the structure.

On basifying an aqueous solution of the hydrochloride with sodium hydroxide or potassium hydroxide, the free base form, l-benzyloxy-2,3-diisopropylguanidine,' is obtained.

Following the procedure of Example 16 but substituting N-methylbenzyl-oxyarnine for benzyloxyamine, there is obtained l-benzyloxy-1-methyl-2,3-diisopropylguanidine hydrochloride. By basifying an aqueous solution of the hydrochloride, the corresponding free base is obtained.

I claim:

1. A compound selected from the group consisting of the free base and acid addition salt forms of a compound of the formula B1 NR2 R3 wherein R is selected from the group consisting of aralkyl and aryloxyalkyl, wherein the aryl moiety of R is substituted by up to three substituents selected from the group consisting of hydrogen, alkyl of from one to four carbon atoms, inclusive, alkoxy, chlorine, bromine, nitro and phenyl; R R R and R are selected from the group 13 consisting of hydrogen and alkyl of from one to four carbon atoms, inclusive.

2. A compound selected from the group consisting of the free base and acid addition salt forms of l-benzyloxyguanidine.

3. l-benzyloxyguanidine cyclohexanesulfamate.

4. A compound selected from the group consisting of the free base and acid addition salt forms of 1-(2-phenylethoxy) guanidine.

5. A compound selected from the group consisting of the free base and acid addition salt forms of l-(l-phenylethoxy guanidine.

6. A compound selected from the group consisting of the free base and acid addition salt forms of l-(3-phenylpropoxy) guanidine.

7. 1-(3-phenylpropoxy)guanidine nitrate.

8. A compound selected from the group consisting of the free base and acid addition salt forms of 1-(2-methyl- 2-phenylethoxy) guanidine.

9. A compound selected from the group consisting of the free base and acid addition salt forms of l-(4-methylbenzyloxy) guanidine.

10. A compound selected from the group consisting of the free base and acid addition salt forms of 1-(4-methoxybenzyloxy) guanidine.

11. A compound selected from the group consisting of the free base and acid addition salt forms of 1-(4-chlorobenzyloxy) guanidine.

12. A compound selected from the group consisting of the free base and acid addition salt forms of 1-(2,6-dichlorobenzyloxy) guanidine.

13. A compound selected from the group consisting of the free base and acid addition salt forms of l-benzhydryloxyguanidine.

14. A compound selected from the group consisting of the free base and acid addition salt forms of 1-(3,3-diphenylpropyoxy) guanidine.

15. A compound selected from the group consisting of the free base and acid addition salt forms of 1-(2-phenoxyethoxy guanidine.

16. 1-(2-phenoxyethoxy)guanidine free base.

17. A compound selected from the group consisting of the free base and acid addition salt forms of 1-(4-phenylbenzyloxy guanidine.

18. A compound selected from the group consisting of the free base and acid addition salt forms of 1-[2-(4-biphenyloxy)ethoxy] guanidine.

19. A compound selected from the group consisting of the free base and acid addition salt forms of l-benzyloxy- 1-methylguanidine.

20. A compound selected from the group consisting of the free base and acid addition salt forms of l-benzyloxy- 3,3-dirnethylguanidine.

21. A compound selected from the group consisting of the free base and acid addition salt forms of l-benzyloxy- 2,3-diisopropylguanidine.

22. l-benzyloxy 2,3 diisopropylguanidine hydrochloride.

23. 1 (3 phenylpropoxy)guanidine cyclohexanesulfamate.

References Cited by the Examiner Fuller et al.: Journal Chemical Society London, 1947, pp. 963-9.

Nyberg et al.: Journal American Chemical Society, vol. 78, pages 781-3 (1956).

CHARLES B. PARKER, Primary Examiner.

R. V. HINES, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,304,324 February 14, 1967 Edward L. Schumann It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below Column 1 line 42 for "malei" read maleic column 3, line 67, for "mixtureof" read mixture of column 8, line 74, for "naprthylmethoxyamine" read napthylmethoxyamine column 9, line 3, for "chlorobenzylamine" read chlorobenzyloxyamine column 13, line 18, for "l-[Z-methyl" read l-(l-methyl column 14, line 3, for "l-(3,3-diphenylpropyoxy)" read l-(3,3-diphenylpropoxy) Signed and sealed this 7th day of November 1967.

(SEAL) Attest:

EDWARD J BRENNER Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Officer 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE FREE BASE AND ACID ADDITION SALT FORMS OF A COMPOUND OF THE FORMULA 